Over 12 million Americans have chronic obstructive pulmonary disease (COPD). Although approximately 1 out of 5 cigarette smokers develop COPD, smoking accounts for 90% of development of COPD. We have evidence that the expression of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is suppressed in human samples from COPD patients and that cigarette smoke reduces the expression of CFTR in lung epithelial cells. CFTR is a chloride channel that is primarily expressed in epithelial cells where it regulates fluid homeostasis. Loss of CFTR function is associated with accumulation of mucus in the lung, abnormal inflammation and wound repair. Therefore, the potential importance of cigarette smoke-induced CFTR abnormalities in the pathophysiology of smoking-related diseases should be further evaluated. Over 10 million Americans are asymptomatic carriers of one CFTR mutation. This implicate that cigarette smoking will further decrease CFTR protein expression and might lead to increased risk of pulmonary diseases. This study will assess the contribution of CFTR to the development of COPD using a mouse model expressing reduced or no CFTR protein. This proposal will also identify the role of CFTR in lung responses to cigarette smoking. These studies will identify new markers that could be targeted for therapy.